DESCRIPTION: (Applicant's Abstract) This is a request for a K05 Senior Scientist Award, which will serve as a continuation of the K02 Independent Scientist Award I currently hold. During the past decade some important developments in the field of cannabinoid research have placed it in the center of biomedical research. The availability of the K02 Award during the past nine years has allowed me to expand my scientific activities in this field in order to meet this exciting challenge. The K05 Award will make it possible for me to continue this highly effective effort. It will also provide me with the opportunity to introduce novel exciting approaches and technologies in my research including a) the use of mass spectrometry to determine the structural features of cannabimimetic protein binding sites; b) the use of molecular biological and genomics approaches in search for novel cannabimimetic targets; c) the use of state of the art multidimensional NIVIR techniques to study the interaction of cannabimimetic agents with their sites of action; d) the development of novel in vivo imaging approaches. The proposed research is directed towards understanding the molecular basis of cannabinoid activity. Cannabinoids and other cannabimimetic agents produce a complex pattern of pharmacological actions many of which are believed to be elicited through an "endogenous cannabinoid biochemical system." This involves two families of endogenous ligands (endocannabinoids) represented by anandamide and 2-arachidonylglycerol (2-AG), both of which induce their physiological responses by interacting with at least two cannabinoid receptors (CB1 and C132). The endocannabinoid system is also modulated by the anandamide amidase which catalyzes the enzymatic deactivation of the endocannabinoid ligands and the recently discovered transporter system (AT) which is involved in the reuptake of the endocannabinoids. Cannabinoids and cannabimimetic drugs induce their receptor-based effects by modulating the functions of one or more of the above four known "cannabimimetic targets." The work to be carried out under the auspices of this award involves a multifaceted approach involving ligand design and synthesis, biophysical and computational chemistry as well as biochemical methods. It will seek to gain information on the interactions of cannabimimetic ligands with each of the four cannabimimetic targets. The results should reveal the molecular properties required for cannabimimetic activity (pharmacophoric requirements) within in the known cannabimimetic classes and serve as the basis for the design of more effective ligands and therapeutic drugs.